MicroRNAs in Prion Diseases—From Molecular Mechanisms to Insights in Translational Medicine

Abstract

MicroRNAs (miRNAs) are small non-coding RNA molecules able to post-transcriptionally regulate gene expression via base-pairing with partially complementary sequences of target transcripts. Prion diseases comprise a singular group of neurodegenerative conditions caused by endogenous, misfolded pathogenic (prion) proteins, associated with molecular aggregates. In humans, classical prion diseases include Creutzfeldt–Jakob disease, fatal familial insomnia, Gerstmann–Sträussler–Scheinker syndrome, and kuru. The aim of this review is to present the connections between miRNAs and prions, exploring how the interaction of both molecular actors may help understand the susceptibility, onset, progression, and pathological findings typical of such disorders, as well as the interface with some prion-like disorders, such as Alzheimer’s. Additionally, due to the inter-regulation of prions and miRNAs in health and disease, potential biomarkers for non-invasive miRNA-based diagnostics, as well as possible miRNA-based therapies to restore the levels of deregulated miRNAs on prion diseases, are also discussed. Since a cure or effective treatment for prion disorders still pose challenges, miRNA-based therapies emerge as an interesting alternative strategy to tackle such defying medical conditions.

microRNA-146a as a biomarker for transmissible spongiform encephalopathy

“…For miRNA-146a quantitation using Northern dot blot arrays, total radiolabeled sncRNA from control or prion-associated brain tissues and/or CSF was probed against miRNA-146a dot-blot panels spotted onto an 8 × 12 array pattern and containing fixed amounts of synthetic human miRNA-146a targets as previously described [11][12][13][14]29]. Using a vacuum dot blot apparatus synthesized miRNA-146a (Integrated DNA Technologies; Coralville, Iowa, USA; 1-800-328-2661; LC Sciences, Houston TX) was spotted onto GeneScreen Plus nylon membranes using a Biomek 2000 labora-tory automated workstation (Beckman, Fullerton, CA).…”

“…SJL/J SWISS ALBINO C57BL/6J SJL/J SWISS ALBINO Folia Neuropathologica 2022; 60/1 miRNA-146a in experimental prion disease one important example cytokine IL-1β, Aβ42 peptide and/or hydrogen peroxide-induced reactive oxygen species (ROS; stressors known to be overly abundant in AD brain) were found to specifically upregulate miRNA-146a in transgenic murine models for AD (TgAD) [35]; miRNA-146a is known to selectively target the 3'-untranslated region (3'-UTR) of the messenger RNA (mRNA) that encodes complement factor H (CFH) and in doing so down-regulates the expression of this large, soluble complement control glycoprotein [28,35]. Decreased CFH contributes to loss of complement and innate-immune system control and increased pro-inflammatory signaling in the brain and CNS and contributes directly to progressive neurodegeneration [11,14,21,24,25]. In this report we quantified the abundance of miRNA-146a in the pre-symptomatic and symptomatic phases of experimental scrapie in the brain and CSF of 3 strains of prion-infected mice and found a graded progression of increased miRNA-146a abundance.…”

“…Typically, activated microglia accumulate within the immediate vicinity of abnormal PrPsc aggregates and release cytokines that play important roles in the inflammatory pathogenesis of PrDs [14,21,[23][24][25]. These include the up-regulation of genes that promote pro-inflammatory pathological signaling and innate-immune system deficits that impact synaptic integrity [8,11,19]. As aggregates of PrPsc progressively accumulate they further induce inevitably fatal neuro-degenerative disease conditions including neuroinflammation typically discernable by massive microglial activation, and proliferation and the subsequent and self-reinforced up-regulation of cytokines such as interleukin 1α (IL-1α) and 1β (IL-1β), glial fibrillary acidic protein (GFAP), tumor necrosis factor α (TNF-α) and astrogliosis accompanied by multiple additional pathological changes in the neuronal transcriptome many of which target synaptic structure and function [15,19,[23][24][25]39].…”

“…Unfortunately, all human PrD clinical trials have failed to show any significant survival benefit [43,47]. As mentioned earlier, PrDs appear to involve neuropathological pro-inflammatory changes that accompany alterations in neuronal and synaptic function from initial asymptomatic stages and a considerable prodromal period before the sudden onset of rapid cognitive decline, inflammatory neurodegeneration, insidious global CNS dysfunction, functional collapse and death [11,23,29,39]. Reliable biomarkers enabling early PrD diagnosis, prognosis and the gauging of the effectiveness of potential PrD treatments are therefore needed to increase the time window for remedial therapeutic intervention and clinical management of TSEs.…”

New RNA-Based Breakthroughs in Alzheimer’s Disease Diagnosis and Therapeutics

“…This strategy allows the reduction in the amount of target protein, instead of only inhibiting their activity. miRNA can also target multiple genes, allowing targeting not only one pathologic pathway but the whole disease network [ 58 , 109 , 110 ]. As previously discussed, despite the requirements for tight control, this feature can also make a great difference in the complex and multifactorial AD.…”